Retrosynthetic analysis synthons

The second edition of this extremely successful guidebook for planning organic syntheses is addressed to advanced undergraduate, graduate and research chemists. Retrosynthetic analysis and the synthon approach are presented. This new, extensively revised and enlarged edition takes account of recent developments, such as nanometer-size architecture, while emphasizing the essentials. 

If a target aminodicarboxyl units bears an aryl group in one of its side chains, retrosynthetic analysis indicates that a bromoamide synthon 12, bearing an aliphatic side-chain, should react with a nucleophilic partner carrying the aromatic side chain. In the alternative bromoamide 21, HBr elimination to cinnamic derivatives competes with the desired bromine substitution. 

Retrosynthetic analysis may identify a need to use synthetic equivalent groups. These groups are synthons that correspond structurally to a subunit of the target structure, but in which the reactivity of the functionality is masked or modified. As an example, suppose the transformation shown below was to be accomplished. 

A retrosynthetic analysis leads to one synthon with reversed polarity and another with normal polarity ... 

The principal exponent of the non-computerised approach to retrosynthetic analysis in organic synthesis, and which finds its origin in the early work of E. J. Corey, is S. Warren.5c d A useful shorter account is to be found in the writings of J. Fuhrhop and G. Penzlin.5 The non-computerised retrosynthetic analysis has also been termed the synthon approach, a term which was first introduced and defined by E. J. Corey.15... 

A retrosynthetic analysis of an a,/J-unsaturated aldehyde or ketone involves an initial functional group interconversion into a /1-hydroxycarbonyl compound, followed by a disconnection into the carbocation (12) and the carbanion (13) synthons. The reagent equivalents of these two synthons are the corresponding carbonyl compounds. 

This time-honoured view of ring construction preceded the retrosynthetic approach it is still of value since it provides an indication of which bonds could be selected for disconnection. The more rigorous application of the principles of retrosynthetic analysis leads of course to the formulation of synthons and their reagent equivalents. 

A retrosynthetic analysis of (50) and (52) involving disconnection at both carbon-heteroatom bonds reveals hexane-2,5-dione as the four-carbon fragment needed for ring assembly ring construction is thus of type (45). The most convenient reagents for the appropriate heteroatom synthons are ammonium carbonate and phosphorus pentasulphide (Expts 8.11 and 8.13). 

A retrosynthetic analysis for coumarin reveals salicylaldehyde and acetic anhydride (under basic conditions) as suitable reagent equivalents of the derived synthons. 

The disconnection or synthon approach now integrated into the text, and the principles of retrosynthetic analysis applied to relevant aliphatic, aromatic, alieyelic and heterocyclic compounds. 

Retrosynthetic Analysis — One-Step Disconnections. For each of the following compounds, suggest a one-step disconnection. Use FGIs as needed. Show charge patterns, the synthons, and the corresponding synthetic equivalents. 

Retrosynthetic analysis. Outline a retrosynthetic scheme for the following target molecules. Show (1) the analysis (including FGI, synthons, synthetic equivalents) and (2) the synthesis of each TM. You may only use compounds with five or fewer carbons as starting materials. 

Corey (E.J Corey Pure Appl Chem 1969,14, 30) introduced the term synthon in 1969 when he published his innovative strategies for the construction of complex molecules by considering a retrosynthetic analysis. Later on, Hanessian s (Total Synthesis of Natural Products The Chiron Approach Pergamon Press, 1983) introduction in 1983 of the term Chiron referring to chiral synthons became the general strategy of carbohydrate like symmetry in new molecular targets of many natural products. 

The initial retrosynthetic analysis for a route to travoprost, using the Newton-Roberts route, provided three key synthons a) the a-chain was derived from the commercially available Wittig salt, (4-carboxybutyl)triphenylphosphonium bromide b) the co-chain required a route to the single enantiomer mixed cuprate reagent, most conveniently derived from the propargylic alcohol via the trans-vinyl iodide, to be developed and c) the cyclopentane core could be derived from the single enantiomer protected bromohydrin (Figure 30.3).llc 25... 

In performing a retrosynthetic analysis, it may also be useful to disconnect a bond, showing the fragments not as real compounds but only as an electrophile and a nucleophile. (The electrophile and nucleophile fragments are called synthons.) This may help bring to mind other reactions that can be used to reassemble the fragments. Thus, the disconnection of 3-methyl-1-phenyl-1-butanol can be written as shown in the following equation ... 

Synthons (Section 23.5) Electrophilic and nucleophilic fragments generated by bond disconnections during retrosynthetic analysis. 

Once the retrosynthetic analysis is done, we can go back and use our knowledge of chemistry to think of reagents corresponding to these synthons. Here, for example, we should certainly choose the anion of the phenol as the nucleophile and some functionalized acetic acid molecule with a leaving group in the a position,... 

The diversity in nucleophilic and their complementary electrophilic reagents, in conjunction with the variability of methods for their coupling, simplifies the problem of finding an appropriate reagent for a particular structural context. In fact, the fruitfulness of retrosynthetic analysis in planning real synthetic pathways depends to a substantial extent upon the abundance of alternative synthons, corresponding reagents, and the reliability of the respective synthetic procedures. 

This retrosynthetic analysis corresponds to a somewhat bizarre disconnection of the target structure 92 into a pair of strange C5 (95a) and Cg (96a) synthons. 

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